Scleroderma is a difficult to treat and poorly understood autoimmune condition characterized by dermal and visceral fibrosis, sympathetic overactivity in the form of Raynaud?s phenomenon, and the accumulation of scar- promoting innate immune cells such as macrophages. Despite the well accepted clinical relationship between these entities, a mechanistic link has been neither proposed nor shown. Because we have a longstanding interest in the role of neuronal guidance proteins (NGPs) such as Netrin-1 in SSc-ILD, we decided to study whether Netrin-1 could connect these processes. Netrin-1 is a secreted, laminin-like protein that through attractive and repulsive interactions with dependence receptors regulates critical events in injury, inflammation, remodeling, and repair. In the developing CNS, NTN-1 guides the migration of axons, and in the periphery NTN- 1 guides both postnatal adrenergic innervation and sensory nerve regeneration via interactions with its attractive receptor deleted in colorectal carcinoma (DCC). However, despite growing interest in nerve associated mechanisms of injury and repair in peripheral organs, essentially nothing is known about how NTN-1 interacts with adrenergic innervation in the fibrotic lung and, while nerve-derived signals are increasingly recognized as regulators of macrophage function, the process by which macrophages might reciprocally maintain and remodel adrenergic nerves in the healthy and diseased lung is obscure. Given SSc?s known association with sympathetic dysfunction, better understanding of how adrenergic nerves are remodeled and maintained in SSc-ILD could allow fundamental insights into the neuroscience of fibrosis. In this application we use mouse modeling and SSc-ILD tissues to demonstrate aberrant adrenergic innervation, augmented Noradrenaline (NA), and NA- responsive fibroblasts in the fibrotic lung. These factors interact to drive fibrosis, which can be inhibited via chemical sympathectomy, pharmacologic inhibition of alpha1 adrenergic receptors, or specific deletion of NTN- 1 from macrophages. These findings support the hypothesis that macrophage derived signals such as Netrin-1 foster profibrotic adrenergic nerve remodeling in the lung and will be explored in three aims. This application unites world class investigators in lung biology, scleroderma, innate immunity, adrenergic innervation, Netrin-1, and neuroscience to conduct an integrated project using two animal models, cell specific knockout mice, shielded bone marrow chimeras, pharmacologic receptor activation and inhibition, ex vivo study of human cells and tissues, precision cut lung slices, single cell sequencing approaches, and microCT. Aim 1 will determine the mechanism through which adrenergic nerve derived NA drives pulmonary fibrosis. Aim 2 will determine the mechanism(s) through which Netrin-1+ macrophages regulates pulmonary fibrosis. Aim 3 will define how macrophage derived Netrin-1 controls post-injury adrenergic nerve remodeling. These studies have the potential to produce paradigm shifting results that will change the way we view fibrosis and potentially develop new treatments for SSc-ILD.